tbuckley/cabot-search huggingface dataset:
Abstract 1234: PD-L1 PET: A potential biomarker of checkpoint inhibitor sensitivity in renal cancer
Authors: Aditi Mulgaonkar, Layton Woolford, Roy Elias, Kien Nham, Bing Guan, Guiyang Hao, Christina Stevens, Vanina Toffessi Tcheuyap, Sydney Haldeman, Jeffrey Miyata, Deyssy Carrillo, Qian (Janie) Qin, Nirmish Singla, Isaac Bowman, Jeffrey Cadeddu, Vitaly Margulis, Alana Christie, Payal Kapur, Ivan Pedrosa, Marianna Dakanali, Orhan Oz, Xiankai Sun, James Brugarolas
Journal: Cancer Research (2022)

Abstract Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy. Program death-ligand 1 (PD-L1) and its corresponding receptor (PD-1) are the target of most FDA-approved ICIs. Perhaps unsurprisingly, PD-L1 levels are predictive of response to targeting drugs in lung and other cancers. However, PD-L1 is not predictive in other tumor types including renal cell carcinoma (RCC). PD-L1 is typically measured on tumor biopsies or archival tissues and we hypothesized that the lack of PD-L1 predictive power is due to tumor heterogeneity and tumor evolution. To test this notion, we embarked upon the generation of a PD-L1 probe that would enable real time assessment of PD-L1 across sites of disease using molecular imaging. We leveraged atezolizumab, a highly specific PD-L1 therapeutic antibody with a mutant Fc. Atezolizumab (ATZ) was labeled with 89Zr after conjugation with a bifunctional chelator and evaluated by positron emission tomography (PET). In extensive preclinical studies using multiple patient-derived xenografts (PDXs) with variable PD-L1 levels, we show that 89Zr-ATZ PET is able to distinguish RCC with variable PD-L1 expression. These data set the foundation for an investigator new drug (IND) approval from the FDA and an ongoing clinical trial in RCC patients (NCT04006522). Consistent with our hypothesis, 89Zr-ATZ PET shows substantial PD-L1 heterogeneity not only across but also within patients at different sites of disease. Furthermore, preliminary data suggest that PD-L1 levels may be predictive of response to ICI. By assessing PD-L1 expression in real time, 89Zr-ATZ PET may enable: (1) the identification of patients most likely to respond to PD-L1/PD-1 targeted therapies; (2) tailored management of the disease across different sites; (3) the evaluation of interventions that modulate PD-L1 levels; (4) insights into toxicities; and (5) probing resistance. Citation Format: Aditi Mulgaonkar, Layton Woolford, Roy Elias, Kien Nham, Bing Guan, Guiyang Hao, Christina Stevens, Vanina Toffessi Tcheuyap, Sydney Haldeman, Jeffrey Miyata, Deyssy Carrillo, Qian (Janie) Qin, Nirmish Singla, Isaac Bowman, Jeffrey Cadeddu, Vitaly Margulis, Alana Christie, Payal Kapur, Ivan Pedrosa, Marianna Dakanali, Orhan Oz, Xiankai Sun, James Brugarolas. PD-L1 PET: A potential biomarker of checkpoint inhibitor sensitivity in renal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1234.
Abstract 2815: Exploring the role of telomerase in senescence and exhaustion in CAR T cell immunotherapy
Authors: Tara Murty, Maria C. Ramello, Elena Sotillo, Lu Chen, Steven A. Artandi, Crystal L. Mackall
Journal: Cancer Research (2022)

Abstract Chimeric antigen receptor (CAR) T cell therapy has revolutionized oncology through engineered targeting of antigens on previously untreatable cancers. However, less than half of patients on CAR T cell therapy experience long-term disease control, with better outcomes observed in pediatric compared to adult populations. Senescent T cells have been shown to manifest defective killing abilities and the development of negative regulatory functions, with evidence suggesting that senescence may play a role in decreasing CAR T cell efficacy and persistence. Moreover, levels of telomerase have been shown to control the lifespan of human T cells, with increased levels delaying senescence. It has been shown that T cell exhaustion limits CAR T cell efficacy in the context of solid tumors, where CAR T cells have yet to demonstrate sustained responses. Using a model of CAR T cell exhaustion developed in our lab, and CAR T cells manufactured from younger and older donors, we have developed a comprehensive method to profile T cell functionality, phenotype, and proliferation. We are able to characterize features of senescence via cell surface markers, intracellular activity, telomere length, and telomerase activity as well as features of exhaustion. Using CRISPR/Cas9, we have inactivated TERT in primary human T cells and CAR T cells and interrogated the effects of hTERT knockout as well as of hTERT overexpression on key markers of T cell identity, exhaustion, senescence, and cytotoxic activity. Understanding telomerase in the context of CAR T cell therapy will provide mechanistic insights into senescence and exhaustion cellular programs and has the potential to inform increasingly effective CAR T cell cancer treatments. Citation Format: Tara Murty, Maria C. Ramello, Elena Sotillo, Lu Chen, Steven A. Artandi, Crystal L. Mackall. Exploring the role of telomerase in senescence and exhaustion in CAR T cell immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2815.
Abstract 3990: MERTK is a potential therapeutic target in Ewing sarcoma
Authors: Sherri K. Smart, Tsz Y. Yeung, Xiaodong Wang, Stephen V. Frye, H. Shelton Earp, Douglas K. Graham, Deborah DeRyckere
Journal: Cancer Research (2022)

Abstract Ewing sarcoma (EWS) is the second most common pediatric bone tumor, and outcomes remain poor in patients with advanced or relapsed disease. In addition, current treatments rely on multi-modal therapy that has significant short- and long-term side effects. New, less toxic and more effective treatments are urgently needed. One potential therapeutic target is the receptor tyrosine kinase MERTK. MERTK is overexpressed in numerous cancers where it promotes tumor cell survival, metastasis, and resistance to cytotoxic and targeted therapies. We demonstrated expression and phosphorylation of MERTK protein in 5 of 5 EWS family cell lines tested. Stimulation with the MERTK ligand GAS6 resulted in activation of downstream oncogenic signaling pathways, including JAK/STAT and MAPK/ERK. Moreover, publicly available data from CRISPR-based library screens suggest that EWS cell lines are particularly dependent on MERTK. Thus, therapeutic strategies targeting MERTK may be particularly effective for treatment of EWS. To explore the therapeutic impact of MERTK inhibition in various cancers, we developed MRX-2843, a first-in-class MERTK-selective tyrosine kinase inhibitor that is currently in clinical trials. Treatment with MRX-2843 decreased phosphorylation of MERTK in a dose dependent manner, with an IC50 of 123 nM (95% CI; 53-180 nM) in A673 cells, and reduced downstream STAT6 signaling. In addition, MRX-2843 had potent anti-tumor activity against all 5 EWS cell lines, leading to reduced expansion and decreased cell density in culture with IC50 values ranging from 178 - 297 nM. Of note, inhibition of MERTK phosphorylation correlated with anti-tumor activity in both the A673 and TC106 cell lines, implicating MERTK inhibition as a mechanism of MRX-2843 anti-tumor activity. Together these data validate MERTK as a promising therapeutic target in EWS and support development of MRX-2843 for treatment of EWS, with potential to directly inform and enable a clinical trial in pediatric patients and, ultimately, to improve both outcomes and quality of life for patients with this disease. Citation Format: Sherri K. Smart, Tsz Y. Yeung, Xiaodong Wang, Stephen V. Frye, H. Shelton Earp, Douglas K. Graham, Deborah DeRyckere. MERTK is a potential therapeutic target in Ewing sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3990.
Abstract 6192: ERK/AKT pathways may be the wrong effectors for KRAS signaling inhibition in colorectal cancers
Authors: Peh Yean Cheah, Kuen Kuen Lam, Choong Leong Tang, Emile Tan, Siew Heng Wong
Journal: Cancer Research (2022)

Abstract Colorectal cancer (CRC) is the third highest incident cancer worldwide and a major cause of cancer death. KRAS protein gain-of-function point mutations play major roles in colorectal tumorigenesis. However, direct inhibition of KRAS is challenging as its protein structure is inadmissible to inhibitor docking. Efforts have been diverted to inhibit downstream RAF/MEK/ERK and PI3K/Akt signaling. Nevertheless, none of these inhibitors has progressed to clinical use in CRC despite extensive trials over the past few decades. We examined levels of phospho-ERK1/2(T202/Y204) and phospho-Akt1/2/3(S473) in human colorectal tumor and matched mucosa at least 10 cm away with quantitative near infrared western blot and immunofluorescence imaging. Surprisingly, 75.5% (25/33) of tumors has lower or equivalent phospho-ERK1/2 and 96.9% (31/32) of tumors has lower phospho-AKT1/2/3 compared to matched mucosa, irrespective of KRAS mutation status and tumor stage. In contrast, we discovered KRAS-dependent SOX9 upregulation in 28 of the 31 (90.3%) tumors. CPTAC phosphoproteomics data similarly showed significantly lower phospho-ERK1/2 levels in tumor compared to matched mucosa. Analysis of transcriptome data from TCGA and GEO series GSE95132 also showed no activation of RAF/MEK/ERK signaling in CRC tumors. These data indicate that the pursue of targeted therapy inhibiting RAF/MEK/ERK and PI3K/Akt signaling is unlikely to be effective in sporadic CRC and possibly harmful as phospho-ERK1/2 are highly expressed in the matched mucosa suggesting a role in normal colonic homeostasis. The widespread use of RAF/MEK/ERK or PI3K/Akt signaling downregulation as a biomarker in drug testing on CRC cell lines needs to be re-evaluated. The data suggest further that SOX9 could be an alternative effector and biomarker of KRAS signaling. Citation Format: Peh Yean Cheah, Kuen Kuen Lam, Choong Leong Tang, Emile Tan, Siew Heng Wong. ERK/AKT pathways may be the wrong effectors for KRAS signaling inhibition in colorectal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6192.
Dendrimers as nanoscale vectors: Unlocking the bars of cancer therapy
Authors: Asmita Deka Dey, Ashkan Bigham, Yasaman Esmaeili, Milad Ashrafizadeh, Farnaz Dabbagh Moghaddam, Shing Cheng Tan, Satar Yousefiasl, Saurav Sharma, Aziz Maleki, Navid Rabiee, Alan Prem Kumar, Vijay Kumar Thakur, Gorka Orive, Esmaeel Sharifi, Arun Kumar, Pooyan Makvandi
Journal: Seminars in Cancer Biology (2022)
Abstract 1510: Exposure to butyrate metabolite mediates genomic instability in oropharyngeal keratinocytes
Authors: Eva McGhee, Mengtao Li, Yi-Ling Lin, Brooke Su-Velez, Nefertari Carr, Chinelo Njubigbo, Rohun Sadeghi, Matin Sadegh, Julian Handler, Adin Handler, Naomi Long, Jay Vadgama
Journal: Cancer Research (2022)

Abstract Human Papillomavirus (HPV), a non-enveloped epitheliotropic double stranded DNA virus, is an etiological agent of oral cancer, and can be cleared by host immunity. A small percentage of patients that develop persistent infection with oncogenic HPV show an increased risk of developing an HPV-associated malignancy. Head and neck, oropharyngeal cancer is related to the persistent infection by high-risk HPV type 16, E6/E7 oncoproteins. The E6/E7 oncoproteins significantly contribute to the carcinogenic genomic instability effect of high-risk HPV through the degradation of two proteins, p53 and pRB, respectively. The human oropharynx often harbors anaerobic bacteria that produce a variety of byproducts, including butyrate. Butyrate is a modulator of induced genomic instability, influencing the development of HPV oral cancer when implanted in a syngeneic mouse model. In this study, we investigate butyrate co-treatment with HPV E6/E7 in vitro. This treatment increased cellular proliferation, DNA double strand breaks, and genetic instability processes associated with apoptosis regulation. These data indicate that in connection with butyrate, HPV E6/E7 oncoproteins can promote increased upregulation of apoptosis, disrupt cell cycle regulation, and decrease DNA double strand break repair. Epigenetics and chromosomal instability events have been noted, specifically, the deletion of the distal region of chromosome 11q22-23 in E6/E7 transfected keratinocytes. These results indicate that HPV-16, E6/E7 oncoproteins plus butyrate treatment can influence genomic changes in mouse keratinocytes, which may further promote oral carcinogenesis. Citation Format: Eva McGhee, Mengtao Li, Yi-Ling Lin, Brooke Su-Velez, Nefertari Carr, Chinelo Njubigbo, Rohun Sadeghi, Matin Sadegh, Julian Handler, Adin Handler, Naomi Long, Jay Vadgama. Exposure to butyrate metabolite mediates genomic instability in oropharyngeal keratinocytes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1510.
Association of State Medicaid Expansion Status With Rates of Suicide Among US Adults
Authors: Hetal Patel, Justin Barnes, Nosayaba Osazuwa-Peters, Laura Jean Bierut
Journal: JAMA Network Open (2022)

<h3>Importance</h3> In the US, suicide is the 10th leading cause of death and a serious mental health emergency. National programs that address suicide list access to mental health care as key in prevention, and more large-scale policies are needed to improve access to mental health care and address this crisis. The Patient Protection and Affordable Care Act (ACA) Medicaid Expansion Program was implemented in several states with the goal of increasing access to the health care system. <h3>Objective</h3> To compare changes in suicide rates in states that expanded Medicaid under the ACA vs states that did not. <h3>Design, Setting, and Participants</h3> In this cross-sectional study, state-level mortality rates were obtained from the National Center for Health Statistics for US individuals aged 20 to 64 years from January 1, 2000, to December 31, 2018. Data analysis was performed from April 18, 2021, to April 15, 2022. <h3>Exposures</h3> Changes in suicide mortality rates among nonelderly adults before and after Medicaid expansion in expansion and nonexpansion states were compared using adjusted difference-in-differences analyses via hierarchical bayesian linear regression. <h3>Main Outcomes and Measures</h3> Suicide rates using death by suicide as the primary measure. <h3>Results</h3> Of the total population at risk for suicide, 50.4% were female, 13.3% were Black, 79.5% were White, and 7.2% were of other races. The analytic data set contained suicide mortality data for 2907 state-age-year units covering the general US population. A total of 553 912 deaths by suicide occurred during the study period, with most occurring in White (496 219 [89.6%]) and male (429 580 [77.6%]) individuals. There were smaller increases in the suicide rate after 2014 in Medicaid expansion (2.56 per 100 000 increase) compared with nonexpansion states (3.10 per 100 000 increase). In adjusted difference-in-differences analysis, a significant decrease of −0.40 (95% credible interval, −0.66 to −0.14) suicides per 100 000 individuals was found, translating to 1818 suicides that were averted in 2015 to 2018. <h3>Conclusions and Relevance</h3> In this cross-sectional study, although suicide rates increased in both groups, blunting of these rates occurred among nonelderly adults in the Medicaid expansion states compared with nonexpansion states. Because this difference may be linked to increased access to mental health care, policy makers should consider suicide prevention as a benefit of expanding access to health care.
Abstract 2557: Slit2 inhibits small cell lung cancer by targeting tumor microenvironment
Authors: Dinesh K. Ahirwar, Manish Charan, Swati Misri, Konstantin Shilo, Ramesh Ganju
Journal: Cancer Research (2022)

Abstract Small cell lung cancer (SCLC) is the deadliest subtype of lung cancer with a 5-year survival rate of &amp;lt;5% in extensive-state disease and is designated by US Congress as a “recalcitrant cancer”. Recently approved by FDA, immune checkpoint blockade (ICB) immunotherapy showed marginally improved survival and only in a few patients, suggesting an inert immune tumor microenvironment (TME) and the existence of SCLC subtypes. Therefore, there is a significant need to develop more effective therapies for SCLC. In addition to the nearly universal biallelic inactivation of Rb and Tp53 genes in human SCLC tumors, comprehensive genome-wide screening studies have identified major co-occurring mutations in PTEN, CREBBP, EP300, SLIT2, MLL, COBL, and EPHA7 genes. Among them, SLIT2 showed the highest level of genomic abnormalities defined by a pronounced clustering of mutations and frequent genomic loss. However, the role of Slit2 in SCLC has not been defined yet. By using genetically engineered human SCLC cells overexpressing Slit2 or recombinant Slit2 (rSlit2) protein, we show that Slit2 inhibits SCLC cells proliferation, migration, and invasion properties and tumor sphere formation ability of drug-resistant SCLC cells in vitro. The mechanistic studies have identified inhibition of AKT and β-catenin mediated signaling pathways by Slit2 overexpression. Next, we implanted human SCLC cell lines into the immunocompromised NSG mice subcutaneously followed by treatment with rSlit2 or sterile saline. Analysis of tumor volume over the 4 weeks showed that rSlit2 treatment significantly reduced the growth of SCLC tumors. Further analysis of tumors showed that rSlit2 treated tumors harbor less M2-like CD206+ macrophages. Overall, these results suggest that Slit2 possesses tumor suppressive properties and could be developed as a novel therapeutic agent against SCLC. Citation Format: Dinesh K. Ahirwar, Manish Charan, Swati Misri, Konstantin Shilo, Ramesh Ganju. Slit2 inhibits small cell lung cancer by targeting tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2557.
Abstract 1315: Tumor necrosis factor related apoptosis inducing ligand fosters myeloid derived suppressor cell mediated tumor immune evasion in cholangiocarcinoma
Authors: Emilien Loeuillard, Jingchun Yang, Haidong Dong, Gregory J. Gores, Sumera I. Ilyas
Journal: Cancer Research (2022)

Abstract Background and Aims: Tumor necrosis factor related apoptosis inducing ligand (TRAIL) is predominantly expressed on immune cells. Although TRAIL biology has garnered considerable attention as a potential anti-cancer strategy, TRAIL agonists have had very limited anti-cancer activity in humans. TRAIL signaling can attenuate the T lymphocyte response. However, this potential immunosuppressive function of TRAIL has not been examined in cancer biology. Cholangiocarcinoma (CCA), a highly lethal biliary tract cancer, has a dense immunosuppressive microenvironment. Accordingly, CCA provides a model to examine the potential immune regulatory function of TRAIL in cancer biology. Methods: Using a syngeneic, orthotopic murine model of CCA (PMID: 29464042), murine CCA cells (SB cells) that express both Trail and Trail receptor (Tr) were implanted into livers of WT and Tr-/- mice. Hence, in this model the host immune cells express Trail but not the receptor; therefore, they would be capable of inducing TRAIL-mediated apoptosis in CCA cells but would be resistant to TRAIL-mediated immunosuppression. After 4 weeks of tumor growth, mice were sacrificed, and tumors were characterized using flow cytometry. Results: We observed that Tr-/- mice had a significant reduction in tumor burden compared to WT mice. Moreover, tumor bearing Tr-/- mice had a significant increase in cytotoxic T lymphocytes (CTLs) and enhanced CTL effector function. Myeloid-derived suppressor cells (MDSCs) were significantly decreased in Tr-/- tumors compared to WT tumors. Furthermore, implantation of SB cells devoid of Trail (SB-Trail-/-) into WT mice resulted in a significant reduction in tumor burden and MDSC infiltration. In vitro functional studies employing SB cells deficient in Tr (SB-Tr-/-) and MDSCs were carried out. There was a significant reduction in proliferation and immunosuppressive function of MDSCs when cocultured with SB-Tr-/- compared to SB cells. These results indicate that TRAIL-TR fosters MDSC growth and immunosuppressive function. In conclusion, we have demonstrated that Tr-/- mice have a significant reduction in CCA tumor burden and MDSC infiltration. Consequently, Tr-/- tumors have enhanced CTL infiltration and function. These data suggest that the TRAIL-TR system mediates tumors immune evasion via MDSCs, and direct targeting of TRAIL on CCA cells is a potential anti-tumor strategy. Citation Format: Emilien Loeuillard, Jingchun Yang, Haidong Dong, Gregory J. Gores, Sumera I. Ilyas. Tumor necrosis factor related apoptosis inducing ligand fosters myeloid derived suppressor cell mediated tumor immune evasion in cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1315.